Cell migration and the anatomic control of thymocyte precursor differentiation

The thymus performs several essential functions during the steady-state production of T lymphocytes in adults, including expansion of the precursor pool, differentiation into multiple lineages and screening for TCRs with restricted specificities. Other than those functions attributed to the TCR, most of the factors that control these processes remain undefined. One potential mechanism for such control may, be related to the movement of precursor cells between distinct anatomical compartments in the thymus. Histological studies show that the majority of CD4(-) CD8(-) cells are found in the subcapsular region. However, vascular tissues that support the migration of precursor cells into the thymus (post-capillary venules) are located deep in the tissue, near the cortico-medullary junction. This implies that blood-borne cells entering the thymus must transit outward across the cortex in order to accumulate in the SCR. Differentiation of DN cells into the CD4(+) 8(+) stage correlates with a reversal in polarity and migration inward, while mature cells ultimately transit the CMJ in the opposite direction of cells first entering the organ. Here we review evidence for a model in which differentiation is induced and proliferation is controlled by this progressive translocation of immature precursors through discrete stromal compartments. In addition, we attempt to summarize what is known about the molecular mechanisms that may support polarized migration of early CD4(-) 8(-) thymocytes in the adult, as well as how and where the relevant differentiative and/or proliferative signals may be compartmentalized.